Hantaviruses are rodent-borne bunyaviruses that cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. The viruses form a genus Hantavirus within the Bunyaviridae family. They are negative-strand RNA viruses with a genome consisting of three different segments, S, M, and L. Hantaviruses belong to the group of “emerging viruses” exhibiting an increasing significance as human pathogens. To cause human disease, the viruses have to be transmitted from their respective hosts to men.

There is an urgent need to acquire substantial knowledge about the epidemiology, molecular evolution and clinical relevance of hantaviruses circulating in Central Europe. This thesis presents novel data about two European hantaviruses, Dobrava virus (DOBV) and Tula virus (TULV).

DOBV is an important etiologic agent of HFRS in Europe. DOBV strains were found to be hosted by at least two different rodent species, yellow-necked mouse (Apodemus flavicollis) and striped field mouse (A. agrarius). According to their natural hosts they form the distinct genetic lineages DOBV-Af and DOBV-Aa, respectively. We have determined and analysed the complete S and M, and partial L segment nucleotide sequences of sympatrically occurring DOBV-Af and DOBV-Aa strains from Central Europe. Molecular phylogenetic analyses gave evidence for genetic reassortment in the evolution of the virus species. It will be important to see whether such reassortment processes (similar to the situation in influenza viruses which carry segmented genomes, too) can change the virulence of hantaviruses towards humans.

Whereas for virus strains of the DOBV-Af lineage their pathogenic potential towards humans was known from studies on the Balkans, such evidence was still missing for the newly discovered DOBV-Aa lineage in Central Europe. We were able to amplify a DOBV-Aa nucleotide sequence from a DOBV-seropositive HFRS patient in Central Europe. This is the first molecular identification of human infection by DOBV in Central Europe and the first direct proof that a virus strain related to the DOBV-Aa lineage, carried by A. agrarius rodents, is able to cause HFRS.

For future studies on the virus-host interactions of DOBV-Aa, it was important to isolate a viable virus strain. This urgency was underlined by the fact that the Central European DOBV-Aa strains were shown to be only distantly related to the existing DOBV cell culture isolates from Estonia, Slovenia and Greece. Therefore, under biosafety level 3 conditions, we have established a DOBV isolate named Slovakia (SK/Aa) from an A. agrarius animal captured in Slovakia. SK/Aa, as the only isolate clearly belonging to the DOBV-Aa lineage, can be taken as the representative of this virus lineage. The new virus isolate, in comparison to a DOBV-Af strain, was used for serotyping neutralising antibodies of HFRS patients in Central Europe by the use of a focus reduction neutralisation assay. Most patients' sera exhibited a higher end-point titer towards SK/Aa suggesting that DOBV-Aa strains are responsible for most of the DOBV HFRS cases in this region.

TULV is carried by European common voles (Microtus sp.). Its pathogenic potential for humans was rather unknown. We have described the first case of HFRS which can be associated with TULV infection. Moreover, TULV strains detected in M. arvalis near the home village of the patient in North-East Germany clustered with strains from Poland and represent a new, well-supported genetic lineage within the TULV species. In addition to DOBV and longer known Puumala virus, TULV is most likely an additional causative agent of HFRS in Central Europe.